Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway
Mst1 is a multifunctional serine/threonine kinase that is highly expressed in several immune organs. The role of Mst1 in the activation of dendritic cells (DCs), a key player of adaptive immunity, is poorly understood. In this study, we investigated the role of Mst1 in GM-CSF-induced bone marrow-der...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-09-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02142/full |
| _version_ | 1818777560878678016 |
|---|---|
| author | Kyung-Min Cho Myun Soo Kim Hak-Jun Jung Eui-Ju Choi Tae Sung Kim |
| author_facet | Kyung-Min Cho Myun Soo Kim Hak-Jun Jung Eui-Ju Choi Tae Sung Kim |
| author_sort | Kyung-Min Cho |
| collection | DOAJ |
| description | Mst1 is a multifunctional serine/threonine kinase that is highly expressed in several immune organs. The role of Mst1 in the activation of dendritic cells (DCs), a key player of adaptive immunity, is poorly understood. In this study, we investigated the role of Mst1 in GM-CSF-induced bone marrow-derived DCs and the underlying mechanisms. Mst1−/− DCs in response to GM-CSF expressed higher levels of activation/maturation-related cell surface molecules, such as B7 and MHC class II than Mst1+/+ DCs. Furthermore, the expression of proinflammatory cytokines, such as IL-23, TNF-α, and IL-12p40, was increased in Mst1−/− DCs, indicating that Mst1-deficiency may induce the hyperactivation of DCs. Additionally, Mst1−/− DCs exhibited a stronger capacity to activate allogeneic T cells than Mst1+/+ DCs. Silencing of Mst1 in DCs promoted their hyperactivation, similar to the phenotypes of Mst1−/− DCs. Mst1−/− DCs exhibited an increase in Akt1 phosphorylation and c-myc protein levels. In addition, treatment with an Akt1 inhibitor downregulated the protein level of c-myc increased in Mst1-deficient DCs, indicating that Akt1 acts as an upstream inducer of the de novo synthesis of c-myc. Finally, Akt1 and c-myc inhibitors downregulated the increased expression of IL-23p19 observed in Mst1-knockdown DCs. Taken together, these data demonstrate that Mst1 negatively regulates the hyperactivation of DCs through downregulation of the Akt1/c-myc axis in response to GM-CSF, and suggest that Mst1 is one of the endogenous factors that determine the activation status of GM-CSF-stimulated inflammatory DCs. |
| first_indexed | 2024-12-18T11:30:47Z |
| format | Article |
| id | doaj.art-3313b44a4e3543b59529a837d0ca13de |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-18T11:30:47Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-3313b44a4e3543b59529a837d0ca13de2022-12-21T21:09:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-09-011010.3389/fimmu.2019.02142474702Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc PathwayKyung-Min Cho0Myun Soo Kim1Hak-Jun Jung2Eui-Ju Choi3Tae Sung Kim4Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South KoreaInstitute of Convergence Science, Korea University, Seoul, South KoreaDepartment of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South KoreaDepartment of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South KoreaDepartment of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South KoreaMst1 is a multifunctional serine/threonine kinase that is highly expressed in several immune organs. The role of Mst1 in the activation of dendritic cells (DCs), a key player of adaptive immunity, is poorly understood. In this study, we investigated the role of Mst1 in GM-CSF-induced bone marrow-derived DCs and the underlying mechanisms. Mst1−/− DCs in response to GM-CSF expressed higher levels of activation/maturation-related cell surface molecules, such as B7 and MHC class II than Mst1+/+ DCs. Furthermore, the expression of proinflammatory cytokines, such as IL-23, TNF-α, and IL-12p40, was increased in Mst1−/− DCs, indicating that Mst1-deficiency may induce the hyperactivation of DCs. Additionally, Mst1−/− DCs exhibited a stronger capacity to activate allogeneic T cells than Mst1+/+ DCs. Silencing of Mst1 in DCs promoted their hyperactivation, similar to the phenotypes of Mst1−/− DCs. Mst1−/− DCs exhibited an increase in Akt1 phosphorylation and c-myc protein levels. In addition, treatment with an Akt1 inhibitor downregulated the protein level of c-myc increased in Mst1-deficient DCs, indicating that Akt1 acts as an upstream inducer of the de novo synthesis of c-myc. Finally, Akt1 and c-myc inhibitors downregulated the increased expression of IL-23p19 observed in Mst1-knockdown DCs. Taken together, these data demonstrate that Mst1 negatively regulates the hyperactivation of DCs through downregulation of the Akt1/c-myc axis in response to GM-CSF, and suggest that Mst1 is one of the endogenous factors that determine the activation status of GM-CSF-stimulated inflammatory DCs.https://www.frontiersin.org/article/10.3389/fimmu.2019.02142/fullMst1dendritic cellshyperactivationAkt1c-mycGM-CSF |
| spellingShingle | Kyung-Min Cho Myun Soo Kim Hak-Jun Jung Eui-Ju Choi Tae Sung Kim Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway Frontiers in Immunology Mst1 dendritic cells hyperactivation Akt1 c-myc GM-CSF |
| title | Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway |
| title_full | Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway |
| title_fullStr | Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway |
| title_full_unstemmed | Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway |
| title_short | Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway |
| title_sort | mst1 deficiency induces hyperactivation of monocyte derived dendritic cells via akt1 c myc pathway |
| topic | Mst1 dendritic cells hyperactivation Akt1 c-myc GM-CSF |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02142/full |
| work_keys_str_mv | AT kyungmincho mst1deficiencyinduceshyperactivationofmonocytederiveddendriticcellsviaakt1cmycpathway AT myunsookim mst1deficiencyinduceshyperactivationofmonocytederiveddendriticcellsviaakt1cmycpathway AT hakjunjung mst1deficiencyinduceshyperactivationofmonocytederiveddendriticcellsviaakt1cmycpathway AT euijuchoi mst1deficiencyinduceshyperactivationofmonocytederiveddendriticcellsviaakt1cmycpathway AT taesungkim mst1deficiencyinduceshyperactivationofmonocytederiveddendriticcellsviaakt1cmycpathway |